Download 2. antiarrhythmic drugs

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Cardiac contractility modulation wikipedia , lookup

Hypertrophic cardiomyopathy wikipedia , lookup

Myocardial infarction wikipedia , lookup

Jatene procedure wikipedia , lookup

Antihypertensive drug wikipedia , lookup

Amiodarone wikipedia , lookup

Electrocardiography wikipedia , lookup

Atrial fibrillation wikipedia , lookup

Ventricular fibrillation wikipedia , lookup

Arrhythmogenic right ventricular dysplasia wikipedia , lookup

Heart arrhythmia wikipedia , lookup

Transcript
LECTURE’S OUTLINE:
Electrophysiology of the heart
Arrhythmia: definition, mechanisms,
types
Drugs :class I, II, III, IV
Guide to treat some types of
arrhythmia
Questions
Normal conduction pathway:
1- SA node generates
action potential and
delivers it to the atria
and the AV node
2- The AV node
delivers the impulse
to purkinje fibers
3- purkinje fibers
conduct the impulse
to the ventricles
Other types of
conduction that
occurs between
myocardial cells:
When a cell is
depolarized 
adjacent cell
depolarizes along
Action potential of the heart:
In the atria,
purkinje, and
ventricles the AP
curve consists of
5 phases
In the SA node
and AV node, AP
curve consists of
3 phases
Non-pacemaker action potential
Phase 1: partial
repolarization
Due to rapid efflux of K+
Phase 0: fast
upstroke
Due to Na+
influx
Phase 2: plateu
Due to Ca++
influx
Phase 3:
repolarization
Due to K+ efflux
Phase 4: resting
membrane potential
N.B. The slope of phase 0 = conduction velocity
Also the peak of phase 0 = Vmax
Pacemaker AP
Phase 0: upstroke:
Due to Ca++ influx
Phase 4: pacemaker
potential
Na influx and K efflux
and Ca influx until the
cell reaches threshold
and then turns into
phase 0
Pacemaker cells (automatic cells) have
unstable membrane potential so they can
generate AP spontaneously
Phase 3:
repolarization:
Due to K+ efflux
Effective refractory period (ERP)
It is also called absolute refractory period
(ARP) :
•In this period the cell can’t be excited
•Takes place between phase 0 and 3
Arrhythmia
If the arrhythmia
arises from atria,
SA node, or AV
node it is called
supraventricular
arrhythmia
Causes of
arrhythmia
arteriosclerosis
Coronary artery
spasm
If the arrhythmia
arises from the
ventricles it is
called ventricular
arrhythmia
Heart block
Myocardial
ischemia
Mechnisms of Arrhythmogenesis
1- Abnormal
impulse
generation
Automatic
rhythms
Enhanced
normal
automaticity
↑AP from SA node
Ectopic focus
AP arises from sites
other than SA node
Triggered
rhythms
Delayed
afterdepolarization
Early
afterdepolarization
2-Abnormal
conduction
Conduction
block
1st degree
This is when the
impulse is not
conducted from
the atria to the
ventricles
2nd degree
Reentry
3rd degree
Circus
movement
Reflection
1-This
pathway is
blocked
3-So the cells here will
be reexcited (first by the
original pathway and the
other from the
retrograde)
2-The impulse
from this pathway
travels in a
retrograde fashion
(backward)
Abnormal anatomic conduction
Here is an
accessory
pathway in the
heart called
Bundle of Kent
•Present only in small populations
•Lead to reexcitation  Wolf-Parkinson-White
Syndrome (WPW)
Action of drugs
In case of abnormal generation:
Decrease of phase
4 slope (in
pacemaker cells)
In case of abnormal conduction:
↓conduction
velocity (remember
phase 0)
Before drug
Raises the threshold
after
phase4
↑ERP
(so the cell
won’t be
reexcited
again)
Types of Arrhythmia
Supraventricular Arrhythmias

Sinus Tachycardia: high sinus rate of 100-180
beats/min, occurs during exercise or other conditions
that lead to increased SA nodal firing rate
 Atrial Tachycardia: a series of 3 or more consecutive
atrial premature beats occurring at a frequency >100/min
 Paroxysmal Atrial Tachycardia (PAT): tachycardia which
begins and ends in acute manner
 Atrial Flutter: sinus rate of 250-350 beats/min.
 Atrial Fibrillation: uncoordinated atrial depolarizations.
AV blocks
A conduction block within the AV node , occasionally in the
bundle of His, that impairs impulse conduction from the
atria to the ventricles.
ventricular Arrhythmias




Ventricular Premature Beats (VPBs): caused by
ectopic ventricular foci; characterized by widened QRS.
Ventricular Tachycardia (VT): high ventricular rate
caused by abnormal ventricular automaticity or by
intraventricular reentry; can be sustained or nonsustained (paroxysmal); characterized by widened QRS;
rates of 100 to 200 beats/min; life-threatening.
Ventricular Flutter - ventricular depolarizations
>200/min.
Ventricular Fibrillation - uncoordinated ventricular
depolarizations
Pharmacologic Rationale & Goals

The ultimate goal of antiarrhythmic drug
therapy:
o Restore normal sinus rhythm and conduction
o Prevent more serious and possibly lethal
arrhythmias from occurring.
 Antiarrhythmic drugs are used to:
 decrease conduction velocity
 change the duration of the effective refractory
period (ERP)
 suppress abnormal automaticity
Antyarrhythmic drugs
•Most antiarrhythmic drugs are pro-arrhythmic (promote arrhythmia)
•They are classified according to Vaughan William into four classes according to their
effects on the cardiac action potential
class
I
II
III
IV
mechanism
action
notes
Na+ channel blocker
Change the slope of
phase 0
Can abolish
tachyarrhythmia
caused by reentry
circuit
β blocker
↓heart rate and
conduction velocity
Can indirectly alter
K and Ca
conductance
K+ channel blocker
1. ↑action potential
duration (APD) or
effective refractory
period (ERP).
2. Delay
repolarization.
Inhibit reentry
tachycardia
Ca++ channel blocker
Slowing the rate of rise
in phase 4 of SA
node(slide 12)
↓conduction velocity
in SA and AV node
Class I drugs
Class I
Have moderate K+
channel blockade
IA
They act on open
Na+ channels or
inactivated only
IB
IC
They ↓ conduction velocity in non-nodal
tissues (atria, ventricles, and purkinje fibers)
So they are used
when many Na+
channels are opened
or inactivated (in
tachycardia only)
because in normal
rhythm the channels
will be at rest state
so the drugs won’t
work
Class IA
Quinidine
Slowing of the rate of rise
in phase 0  ↓conduction
velocity
 ↓of Vmax of the cardiac action
potential
 They prolong muscle action
potential & ventricular (ERP)
 They ↓ the slope of Phase 4
spontaneous depolarization
(SA node)  decrease
enhanced normal
automaticity
Procainamide

They make the
slope more
horizontal
Class IA Drugs

They possess intermediate rate of association and
dissociation (moderate effect) with sodium channels.
Pharmacokinetics:
procainamide
quinidine
Good oral
bioavailability
Good oral
bioavailability
Used as IV to
avoid
hypotension
Metabolized
in the liver
Procainamide metabolized into N-acetylprocainamide (NAPA) (active
class III) which is cleared by the kidney (avoid in renal failure)
Class IA Drugs Uses





Supraventricular and ventricular arrhythmias
Quinidine is rarely used for supraventricular
arrhythmias
Oral quinidine/procainamide are used with class III
drugs in refractory ventricular tachycardia patients
with implantable defibrillator
IV procainamide used for hemodynamically stable
ventricular tachycardia
IV procainamide is used for acute conversion of
atrial fibrillation including Wolff-Parkinson-White
Syndrome (WPWS)
defibrillator
Class IA Drugs Toxicity
quinidine
procainamide
AV block
Torsades de
pointes
arrhythmia
because it ↑ ERP
(QT interval)
Shortens A-V nodal
refractoriness (↑AV
conduction) by
antimuscarinic like
effect
↑digoxin
concentration by :
1- displace from
tissue binding sites
2- ↓renal clearance
Ventricular
tachycardia
Asystole or
ventricular
arrhythmia
Hypersensitivity
: fever,
agranulocytosis
Systemic lupus erythromatosus (SLE)-like
symptoms: arthralgia, fever, pleuralpericardial inflammation.
Symptoms are dose and time dependent
Common in patients with slow hepatic
acetylation
Notes:
Torsades de pointes: twisting of the point . Type of
tachycardia that gives special characteristics on ECG
At large dosesof quinidine  cinchonism occurs:blurred vision, tinnitus, headache,
psychosis and gastrointestinal upset
Digoxin is administered before quinidine to prevent the conversion of atrial fibrillation or
flutter into paradoxical ventricular tachycardia
Class IB Drugs
Class IB
lidocaine





mexiletine
They shorten Phase 3
repolarization
↓ the duration of the cardiac
action potential
They suppress arrhythmias
caused by abnormal
automaticity
They show rapid association &
dissociation (weak effect) with
Na+ channels with appreciable
degree of use-dependence
No effect on conduction velocity
tocainide
Agents of Class IB



Lidocaine
Used IV because of extensive
1st pass metabolism
Lidocaine is the drug of choice
in emergency treatment of
ventricular arrhythmias
Has CNS effects: drowsiness,
numbness, convulstion, and
nystagmus
Mexiletine

These are the oral analogs of lidocaine

Mexiletine is used for chronic
treatment of ventricular arrhythmias
associated with previous myocardial
infarction
Adverse effects:
1- neurological effects
2- negative inotropic activity
Uses
They are used in the treatment of ventricular arrhythmias arising during myocardial
ischemia or due to digoxin toxicity
They have little effect on atrial or AV junction arrhythmias (because they don’t act on
conduction velocity)
Class IC Drugs
Class IC
flecainide





They markedly slow Phase 0 fast
depolarization
They markedly slow conduction in
the myocardial tissue
They possess slow rate of
association and dissociation
(strong effect) with sodium
channels
They only have minor effects on
the duration of action potential
and refractoriness
They reduce automaticity by
increasing the threshold potential
rather than decreasing the slope of
Phase 4 spontaneous
depolarization.
propafenone
Uses:
 Refractory ventricular arrhythmias.
 Flecainide is a particularly potent suppressant of premature
ventricular contractions (beats)

1.
2.

Toxicity and Cautions for Class IC Drugs:
They are severe proarrhythmogenic drugs causing:
severe worsening of a preexisting arrhythmia
de novo occurrence of life-threatening ventricular tachycardia
In patients with frequent premature ventricular contraction (PVC)
following MI, flecainide increased mortality compared to
placebo.
Notice: Class 1C drugs are particularly of low safety and have
shown even increase mortality when used chronically after MI
Compare between class IA, IB, and IC drugs as
regards effect on Na+ channel & ERP


Sodium channel blockade:
IC > IA > IB
Increasing the ERP:
IA>IC>IB (lowered)
Because of
K+
blockade
Class II ANTIARRHYTHMIC DRUGS
(β-adrenergic blockers)
Mechanism of action
 Negative inotropic
and chronotropic
action.
 Prolong AV
conduction (delay)
 Diminish phase 4
depolarization 
suppressing
automaticity(of
ectopic focus)
Uses





Treatment of increased
sympathetic activity-induced
arrhythmias such as stressand exercise-induced
arrhythmias
Atrial flutter and fibrillation.
AV nodal tachycardia.
Reduce mortality in postmyocardial infarction patients
Protection against sudden
cardiac death
Class II ANTIARRHYTHMIC DRUGS





Propranolol (nonselective): was proved to
reduce the incidence of sudden arrhythmatic
death after myocardial infarction
Metoprolol
reduce the risk of bronchospasm
selective
Esmolol:
Esmolol is a very short-acting β1-adrenergic
blocker that is used by intravenous route in acute
arrhythmias occurring during surgery or
emergencies
Class III ANTIARRHYTHMIC DRUGS
K+ blockers
Prolongation of phase 3
repolarization without altering
phase 0 upstroke or the resting
membrane potential
 They prolong both the duration
of the action potential and ERP
 Their mechanism of action is
still not clear but it is thought
that they block potassium
channels

Class III
sotalol
amiodarone
ibutilide
Uses:
 Ventricular arrhythmias, especially ventricular
fibrillation or tachycardia
 Supra-ventricular tachycardia
 Amiodarone usage is limited due to its wide
range of side effects
Sotalol (Sotacor)




Sotalol also prolongs the duration of action potential and
refractoriness in all cardiac tissues (by action of K+ blockade)
Sotalol suppresses Phase 4 spontaneous depolarization and
possibly producing severe sinus bradycardia (by β blockade
action)
The β-adrenergic blockade combined with prolonged action
potential duration may be of special efficacy in prevention of
sustained ventricular tachycardia
It may induce the polymorphic torsades de pointes ventricular
tachycardia (because it increases ERP)
Ibutilide
Used in atrial fibrillation or flutter
IV administration
May lead to torsade de pointes
Only drug in class three that possess pure K+ blockade
Amiodarone (Cordarone)





•
•
Amiodarone is a drug of multiple actions and is still not well understood
It is extensively taken up by tissues, especially fatty tissues (extensive
distribution)
t1/2 = 60 days
Potent P450 inhibitor
Amiodarone antiarrhythmic effect is complex comprising class I, II, III,
and IV actions
Dominant effect: Prolongation of action potential duration and refractoriness
It slows cardiac conduction, works as Ca2+ channel blocker, and as a weak
β-adrenergic blocker
Toxicity




Most common include GI intolerance, tremors, ataxia, dizziness, and hyperor hypothyrodism
Corneal microdeposits may be accompanied with disturbed night vision
Others: liver toxicity, photosensitivity, gray facial discoloration, neuropathy,
muscle weakness, and weight loss
The most dangerous side effect is pulmonary fibrosis which occurs in
2-5% of the patients
Class IV ANTIARRHYTHMIC DRUGS
(Calcium Channel Blockers)

Calcium channel blockers decrease
inward Ca2+ currents resulting in a
decrease of phase 4 spontaneous
depolarization (SA node)
 They slow conductance in Ca2+
current-dependent tissues like AV
node.
 Examples: verapamil & diltiazem
Because they act on the heart only
and not on blood vessels.

Dihydropyridine family are not used
because they only act on blood vessels
Mechanism of action

They bind only to depolarized (open) channels  prevention of repolarization
So they act only in cases of arrhythmia because many Ca2+
channels are depolarized while in normal rhythm many of them
are at rest

They prolong ERP of AV node  ↓conduction of impulses from the atria to the
ventricles
Uses
More effective in treatment of atrial than ventricular arrhythmias.
Treatment of supra-ventricular tachycardia preventing the
occurrence of ventricular arrhythmias
Treatment of atrial flutter and fibrillation
contraindication
 Contraindicated in patients with pre-existing
depressed heart function because of their negative
inotropic activity
Adverse effects
 Cause bradycardia, and asystole especially when
given in combination with β-adrenergic blockers
Miscellaneous Antiarrhythmic Drugs
o
o
o
o
Adenosine
Adenosine activates A1-purinergic receptors
decreasing the SA nodal firing and automaticity,
reducing conduction velocity, prolonging
effective refractory period, and depressing AV
nodal conductivity
It is the drug of choice in the treatment of
paroxysmal supra-ventricular tachycardia
It is used only by slow intravenous bolus
It only has a low-profile toxicity (lead to
bronchospasm) being extremly short acting for
15 seconds only
class
ECG QT
Conduction
velocity
Refractory
period
IA
++
↓
↑
IB
0
no
↓
IC
+
↓
no
II
0
III
++
IV
0
↓In SAN and ↑ in SAN and
AVN
AVN
No
↑
↓ in SAN and ↑ in SAN and
AVN
AVN
1st: Reduce thrombus formation by using anticoagulant warfarin
2nd: Prevent the arrhythmia from converting to ventricular arrhythmia:
First choice: class II drugs:
•After MI or surgery
•Avoid in case of heart failure
Second choice: class IV
Third choice: digoxin
•Only in heart failure of left ventricular dysfunction
3rd: Conversion of the arrhythmia into normal sinus rhythm:
Class III:
IV ibutilide, IV/oral amiodarone, or oral sotalol
Class IA:
Oral quinidine + digoxin (or any drug from the 2nd step)
Class IC:
Oral propaphenone or IV/oral flecainide
Use direct current in case
of unstable hemodynamic
patient
Premature ventricular beat (PVB)
First choice: class II
•IV followed by oral
•Early after MI
Second choice: amiodarone
First choice: Lidocaine IV
•Repeat injection
Second choice: procainamide IV
•Adjust the dose in case of renal failure
Third choice: class III drugs
•Especially amiodarone and sotalol
Avoid using
class IC after
MI  ↑
mortality
:‫تجميعات‬
(IA, IC, class III)  torsades de pointes.
Classes II and IV  bradycardia (don’t combine the two)
In atrial flutter use (1st ↓impulses from atria to ventricular to prevent
ventricular tachycardia)
1. Class II
2. Class IV
3. Digoxin.
)‫(على الترتيب‬
2nd convert atrial flutter to normal sinus rhythm use:
1. Ibutilide
2. Sotalol
3. IA or IC.
)‫(على الترتيب‬
If you use quinidine combine it with digoxin or β blocker (because of its anti
muscarinic effect)
Avoid IC in myocardial infarction because it ↑ mortality
1- In ventricular tachycardia and stable hemodynamic which drug to be used?
A- propranolol
B- procainamide
C- quinidine
D- verapamil
2- Mr.Green devloped an arrhythmia and was treated. A month later, he has arthralgia,
fever, pleural inflammation. What was the treatment of arrhythmia?
A- esmolol
B- class III
C- procainamide
D- propafenone
3- Cinchonism occurs with digoxin (F)
A- pulmonary fibrosis
B- bradycardia
diltiazem
amiodarone